Efficacy of an amlodipine/olmesartan treatment algorithm in patients with or without type 2 diabetes and hypertension (a secondary analysis of the BP-CRUSH study).

A prespecified subgroup analysis of an open-label, multicenter, single-arm, dose-titration study is presented. The efficacy and safety of 20-week treatment with an amlodipine (AML)/olmesartan medoxomil (OM)±hydrochlorothiazide (HCTZ) algorithm were assessed in patients with hypertension and type 2 diabetes mellitus (T2DM) who were uncontrolled by antihypertensive monotherapy. Eligible patients received AML/OM 5/20 mg for 4 weeks, followed by stepwise uptitration to AML/OM 5/40 mg, AML/OM 10/40 mg, AML/OM 10/40 mg+HCTZ 12.5 mg and AML/OM 10/40 mg+HCTZ 25 mg at 4-week intervals if blood pressure (BP) remained uncontrolled. The primary end point was the achievement of the seated cuff systolic BP (SeSBP) goal (<140 mm Hg, or <130 mm Hg for patients with T2DM) at week 12. Seated cuff BP was significantly reduced from baseline at all titration dose periods. At week 12, the cumulative SeSBP goal was achieved by 57.9% and 80.1% of patients in the T2DM and non-T2DM subgroups, respectively. Treatment was well tolerated, with low rates of peripheral edema. In summary, switching to a treatment algorithm based on AML/OM±HCTZ after failed monotherapy was safe and improved BP control in patients with hypertension and T2DM.

Are left ventricular mass, geometry and function related to vascular changes and/or insulin resistance in long-standing hypertension? ICARUS: a LIFE substudy.

Vascular hypertrophy and insulin resistance have been associated with abnormal left ventricular (LV) geometry in population studies. We wanted to investigate the influence of vascular hypertrophy and insulin resistance on LV hypertrophy and its function in patients with hypertension. In 89 patients with essential hypertension and electrocardiographic LV hypertrophy, we measured blood pressure; insulin sensitivity by hyperinsulinaemic euglucaemic clamp; minimal forearm vascular resistance (MFVR) by plethysmography; intima-media cross-sectional area of the common carotid arteries (IMA) by ultrasound; and LV mass, relative wall thickness (RWT), systolic function and diastolic filling by echocardiography after two weeks of placebo treatment. LV mass index correlated to IMA/height (r=0.36, P=0.001), serum insulin (r=-0.25, P<0.05), plasma glucose (r=-0.34, P<0.01), and showed a tendency towards a correlation to insulin sensitivity (r=0.21, P=0.051), but was unrelated to MFVR. Deceleration time of early diastolic transmitral flow positively correlated to IMA/height (r=0.30, P<0.01). The ratio between early and atrial LV filling peak flow velocity negatively correlated to MFVR(men) (r=-0.30, P<0.05). Endocardial and midwall systolic LV function were not related to vascular hypertrophy, plasma glucose, serum insulin or insulin sensitivity. In conclusion, insulin resistance was not related to LV hypertrophy or reduced LV function. However, high thickness of the common carotid arteries was associated with LV hypertrophy and high deceleration time of early diastolic transmitral flow. High MFVR was associated with low ratio between early and atrial LV filling peak flow velocity. This may suggest that systemic vascular hypertrophy contributes to abnormal diastolic LV relaxation in patients with hypertension and electrocardiographic LV hypertrophy.

Prehypertension: a possible target for antihypertensive medication.

Vascular changes associated with elevated blood pressure may precede the clinical diagnosis of hypertension. Even after the diagnosis is made, associated coronary heart disease and renal disease continue to progress, despite adequate blood pressure control. Early treatment of blood pressure may reduce the incidence of clinical hypertension and reduce the long-term consequences of hypertension. Animal studies have shown that early blood pressure lowering, through blockade of the renin-angiotensin system, prevents long-term hypertension. Prevention is an important goal in the treatment of hypertension. Our best attempts to prevent hypertension use nonpharmacologic methods of diet and exercise. These methods are fraught with difficulties of implementation and compliance that limit their success. Finding novel approaches to prevent hypertension may have a major impact on the incidence of hypertension. We are investigating the effect of 2 years of treatment with an angiotensin receptor blocker (candesartan cilexitil) compared with placebo, followed by 2 years of follow-up, on the incidence of hypertension in patients with high-normal blood pressure. Incidence of hypertension after discontinuation of active treatment will be compared with the incidence in the placebo group. There will be 1000 patients enrolled in the study, which will be completed in 2004.

Blood viscosity, plasma adrenaline and fasting insulin in hypertensive patients with left ventricular hypertrophy. ICARUS, a LIFE Substudy. Insulin CARotids US Scandinavica.

We have seen relationships between whole blood viscosity (WBV) and components of the metabolic cardiovascular syndrome in borderline hypertensive young men and suggested that sympathetic nervous system (SNS) activity may be a mediator. In the present study we aimed to test this hypothesis in established hypertension and to investigate the relationship between WBV and cardiac dimensions. Unmedicated patients (n = 42) with stage II-III hypertension and electrocardiographic left ventricular hypertrophy (LVH) underwent hyperinsulinemic isoglycemic glucose clamp to assess glucose disposal rate (GDR) and echocardiographic studies. WBV, plasma catecholamines and insulin were measured in arterialized venous blood. WBV at high shear rate correlated with baseline plasma adrenaline (r = 0.33, p = 0.04) and fasting insulin (r = 0.34, p = 0.04) while there was a negative trend for GDR (r = -0.21, p = 0.2). WBV at low shear rate correlated with plasma adrenaline (r = 0.49, p = 0.002) and resting heart rate (r = 0.36, p = 0.02). WBV was higher in smokers than in non-smokers (p = 0.02) and in males than in females (p = 0.02). Fasting insulin independently explained 12% of the variation in WBV at high shear, while baseline adrenaline independently explained 17% of the variation in WBV at low shear. Systolic blood pressure explained 31% of the variation in LV mass index. Thus, we demonstrate positive relationships between blood viscosity versus plasma adrenaline and fasting insulin in hypertensive patients with LVH. We suggest that adrenergic activity may increase hematocrit and viscosity and hence reduce insulin sensitivity.

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study. Insulin Carotids US Scandinavia.

BACKGROUND: Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. METHODS: In 88 unmedicated patients with stage II-III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima-media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. RESULTS: IMT was positively correlated to systolic blood pressure (r= 0.26, P < 0.05), whole body glucose uptake index (M/IG; r= 0.22, P< 0.05), age (r= 0.24, P< 0.05) and negatively correlated to body mass index (r= -0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r= -0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = -0.40, P< 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). CONCLUSIONS: High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.

Tachycardia: an important determinant of coronary risk in hypertension.

Heart rate and blood pressure are highly correlated and in large population studies, individuals with high blood pressure tend to have high heart rates. Fast heart rate precedes the development of high blood pressure and serves as an early indicator of coronary heart disease. Not only does the heart rate predict coronary mortality, but also the non-cardiovascular mortality and is, therefore, an overall predictor of longevity. In the Tecumseh Blood Pressure study, we have seen that 37% of all patients with borderline hypertension have the 'hyperkinetic hypertension state', which consists of elevated cardiac output, high heart rate, high sympathetic tone, and decreased parasympathetic tone. In this population, evidence of high heart rate exists in these individuals as children, and persists through early adulthood. This suggests that tachycardia is a reliable marker of high sympathetic tone. High sympathetic tone might be the mechanism whereby heart rate is associated with high insulin, insulin resistance, dyslipidemia, high hematocrit and excess weight. These mechanisms are discussed in details in this review. Tachycardia is a strong risk factor for sudden death and arrythmia. Heart rate, as one of the prime determinants of cardiac work, may contribute to greater cardiac strain. Animal studies have shown that a higher heart rate may be associated with a greater development of atherosclerotic plaque in coronary vasculature. Therefore, heart rate elevation is not merely a sign of underlying pathology, but it may also cause further damage that leads to increased mortality. In the treatment of hypertension, reducing heart rate by pharmacologic and non-pharmacologic measures may have a greater effect on coronary mortality than blood pressure reduction alone.

Sonographic detection of xanthomas in normal-sized Achilles' tendons of individuals with heterozygous familial hypercholesterolemia.

OBJECTIVE: The objective of this study was to evaluate how well high-frequency linear array sonography reveals xanthomas in the Achilles' tendons of individuals with heterozygous familial hypercholesterolemia before the xanthomas enlarge the tendons enough to become palpable. SUBJECTS AND METHODS: Both Achilles' tendons of 23 individuals (18 female and five male; age range, 16-69 years old) who had heterozygous familial hypercholesterolemia but no clinically apparent Achilles' tendon xanthomas were studied with high-frequency linear array sonography. Hypoechoic areas, consistent with xanthomas, were noted. RESULTS: Xanthomas were revealed in 36 (78%) of 46 tendons and 19 (83%) of 23 individuals. CONCLUSION: Sonography reveals Achilles' tendon xanthomas in many individuals with heterozygous familial hypercholesterolemia before the xanthomas are clinically apparent. Because tendon xanthomas in a hypercholesterolemic individual are essentially pathognomonic of heterozygous familial hypercholesterolemia and are a mainstay in its diagnosis, our study suggests that sonography is useful in the early diagnosis of heterozygous familial hypercholesterolemia.

Home blood pressure as a predictor of future blood pressure stability in borderline hypertension. The Tecumseh Study.

We evaluated time-related blood pressure trends in the Tecumseh study participants, none of whom received antihypertensive treatment. At baseline the blood pressures were measured in the field clinic and by self measurement at home (twice daily for 7 days). After a mean of 3.2 +/- 0.42 years, the clinic and home pressure readings were repeated. Nine hundred forty-six subjects had clinic and home blood pressure readings at baseline. Of these 735 (380 men, 355 women; average age, 32 years) also completed the second examination. Blood pressure, morphometric data, and biochemical measures at the first examination were used as predictors of future clinic blood pressures. Five hundred ninety-six subjects were normotensive on both examinations (81%). Of 79 subjects (10.7%) with clinic hypertension (> 140 mg Hg systolic or 90 mm Hg diastolic) at baseline, 38 remained hypertensive ("sustained hypertension") and 41 became normotensive ("transient hypertension") after 3 years. Another 60 normotensives at baseline (10.4%) became hypertensive on second examination ("de novo hypertensives"; incidence; 8.1%). The home blood pressure readings on both examinations were reproducible. The three hypertensive groups had elevated home blood pressure, were overweight, had dyslipidemia, and higher insulin values. Only the home blood pressure proved predictive of subsequent blood pressure trends. A home blood pressure of 128 and 83 mm Hg or higher detected "sustained" hypertension with a 48% sensitivity and 93% specificity. Readings of 120 and 80 mm Hg or lower predicted future normotension with a 45% sensitivity and a 91% specificity. We conclude that self determination of the blood pressure at home is useful in the management of borderline hypertension. An algorithm for the management of these patients is proposed.

Angiotensin mediates forearm glucose uptake by hemodynamic rather than direct effects.

Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (P <.05) and 59% increase in the arteriovenous glucose gradients (P <.05) to maintain a steady glucose utilization (a decrease of 4%, P=NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism.